This invention relates to certain 7-methoxylated 7-acylamidocephalosporins. In particular, this invention relates to certain of such cephalosporins having in the 7-position an .alpha.-carboxyphenylacetamido group, a protected .alpha.-carboxyphenylacetamido group, an .alpha.-sulfophenylacetamido group, a protected .alpha.-sulfophenylacetamido group, an .alpha.-phosphonophenylacetamido group, or a protected .alpha.-phosphonophenylacetamido group. The compounds of this invention have been found to exhibit particular activity against Pseudomonas and Serratia type microorganisms, which microorganisms customarily are, at best, only moderately susceptible to treatment by cephalosporin antibiotics.
Cephalosporin antibiotics having a methoxyl group at the 7-position are known. For example, 7-methoxycephalosporin C and 7-(5-amino-5-carboxyvaleramido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4- carboxylic acid have been obtained by the fermentation of Streptomyces lipmanii and Streptomyces clavuligerus as described in J. Am. Chem. Soc. 93, 2308 (1971).
Additionally, a number of 7-acylamido-7-methoxycephalosporin antibiotics have been prepared by the direct methoxylation procedure described in co-pending application Ser. No. 301,694 filed Oct. 27, 1972, now abandoned and a continuation-in-part of application Ser. No. 222,293 filed Jan. 31, 1972, and now abandoned. According to this method, a 7-acylamidocephalosporin is reacted at about -80.degree.C. with lithium methoxide in methanol, and the product therefrom is reacted with a positive halogen compound such as t-butyl hypochlorite to provide a 7-acylamido-7-methoxycephalosporin.
7-Amino-7-methoxycephalosporanic acid has been prepared by cleavage of 7-methoxycephalosporin C via the phosphorus pentachloride/pyridine/methanol procedure as described in co-pending application Ser. No. 139,914 filed May 3, 1971, and now abandoned.
7-Amino-7-methoxycephalosporin esters can also be prepared by a process which is the subject of co-pending application Ser. No. 381,470 filed July 23, 1973 now U.S. Pat. No. 3,897,424. This process includes the steps of low temperature 7-methoxylation of a 7-(p-nitrobenzyloxycarbamido)cephalosporin ester; reduction of the methoxylation product to an intermediate reduction product; and treatment of the intermediate reduction product with silica gel.
The compounds of this invention are prepared by conventional acylation of the aforedescribed 7-amino-7-methoxycephalosporin esters employing a suitable acylating agent having the reactive .alpha.-substituent appropriately protected. The resulting product may or may not thereafter be cleaved in accordance with recognized techniques in order thereby to produce the corresponding free acid cephalosporin.